title: Efficacy of ganitumab (AMG 479), alone and in combination with rapamycin, in Ewing's and osteogenic sarcoma models.
abstract: Ewing's and osteogenic sarcoma are two of the leading causes of cancer deaths in children and adolescents. Recent data suggest that sarcomas may depend on the insulin-like growth factor type 1 (IGF-1) receptor (IGF1R) and/or the insulin receptor (INSR) to drive tumor growth, survival, and resistance to mammalian target of rapamycin complex 1 (mTORC1) inhibitors. We evaluated the therapeutic value of ganitumab (AMG 479; C(6472)H(10028)N(1728)O(2020)S(42)), an anti-IGF1R, fully human monoclonal antibody, alone and in combination with rapamycin (mTORC1 inhibitor) in Ewing's (SK-ES-1 and A673) and osteogenic (SJSA-1) sarcoma models. IGF1R was activated by IGF-1 but not by insulin in each sarcoma model. INSR was also activated by IGF-1 in the SJSA-1 and SK-ES-1 models, but not in the A673 model where insulin was the preferred INSR ligand. Ganitumab significantly inhibited the growth of SJSA-1 and SK-ES-1 xenografts; inhibition was associated with decreased IGF1R and Akt phosphorylation, reduced total IGF1R and bromodeoxyuridine detection, and increased caspase-3 expression. Ganitumab inhibited rapamycin-induced IGF1R, Akt, and glycogen synthase kinase-3β hyperphosphorylation in each sarcoma model. However, ganitumab in combination with rapamycin also resulted in a marked increase in INSR expression and activity in the SJSA-1 and A673 models. The in vivo efficacy of ganitumab in the two ganitumab-sensitive models (SJSA-1 and SK-ES-1) was significantly enhanced in combination with rapamycin. Our results support studying ganitumab in combination with mTORC1 inhibitors for the treatment of sarcomas and suggest that INSR signaling is an important mechanism of resistance to IGF1R blockade.
authors.affiliation: Oncology Research Therapeutic Area, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. pbeltran@amgen.com
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Beltran
authors.forename: Young-Ah
authors.initials: YA
authors.lastname: Chung
authors.forename: Gordon
authors.initials: G
authors.lastname: Moody
authors.forename: Petia
authors.initials: P
authors.lastname: Mitchell
authors.forename: Elaina
authors.initials: E
authors.lastname: Cajulis
authors.forename: Steven
authors.initials: S
authors.lastname: Vonderfecht
authors.forename: Richard
authors.initials: R
authors.lastname: Kendall
authors.forename: Robert
authors.initials: R
authors.lastname: Radinsky
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Calzone
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007334:Insulin-Like Growth Factor I; C545764:ganitumab; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D053148:Caspase 3; D020123:Sirolimus